6bcs

Publication Abstract from PubMed

Inhibiting the interaction between amyloid-beta (Abeta) and a neuronal cell surface receptor, LilrB2, has been suggested as a potential route for treating Alzheimer's disease. Supporting this approach, Alzheimer's-like symptoms are reduced in mouse models following genetic depletion of the LilrB2 homologue. In its pathogenic, oligomeric state, Abeta binds to LilrB2, triggering a pathway to synaptic loss. Here we identify the LilrB2 binding moieties of Abeta ((16)KLVFFA(21)) and identify its binding site on LilrB2 from a crystal structure of LilrB2 immunoglobulin domains D1D2 complexed to small molecules that mimic phenylalanine residues. In this structure, we observed two pockets that can accommodate the phenylalanine side chains of KLVFFA. These pockets were confirmed to be (16)KLVFFA(21) binding sites by mutagenesis. Rosetta docking revealed a plausible geometry for the Abeta-LilrB2 complex and assisted with the structure-guided selection of small molecule inhibitors. These molecules inhibit Abeta-LilrB2 interactions in vitro and on the cell surface and reduce Abeta cytotoxicity, which suggests these inhibitors are potential therapeutic leads against Alzheimer's disease.

Inhibiting amyloid-beta cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design.,Cao Q, Shin WS, Chan H, Vuong CK, Dubois B, Li B, Murray KA, Sawaya MR, Feigon J, Black DL, Eisenberg DS, Jiang L Nat Chem. 2018 Oct 8. pii: 10.1038/s41557-018-0147-z. doi:, 10.1038/s41557-018-0147-z. PMID:30297750^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.